Peripheral neuropathy as a complication of diabetes mellitus is estimated to afflict about 600,000 patients in the United States. It is the major form of neuropathy in western countries. Current treatment of this neuropathy is directed at better control of blood-glucose, and metabolic regulation of nerve fascicular hexose concentrations through dietary supplementation of myo-inositol and the administration of aldose reductase inhibitors. Unfortunately, clinical experience with these therapeutic regimes has yielded mixed results: a reflection of our incomplete understanding of the etiology of diabetic neuropathy. The major cause of diabetic neuropathy has long been suspected to be microvascular lesion. However, due to the variability of data presented in support of this hypothesis, as well as recent evidence in favor of an alternative explanation (endoneurial accumulation of polyols), the pathogenesis of diabetic neuropathy remains a highly controversial area of research. The nonuniformity in both onset and severity of symptoms in diabetic neuropathy strongly suggest a pathogenetic mechanism(s) influenced by many factors. Most important among these is a disruption of the protection offered peripheral nerve fibers and their associated glial cells by a specialized microenvironment. The underlying hypothesis of this proposal is that an alteration in the endoneurial microvasculature during the early stages of diabetes disturbs the microenvironment of nerve fibers thereby setting the stage for the development of the neuropathy. The proposed investigation is part of a research effort directed at realizing the long-term objectives of defining the pathogenetic mechanism(s) of diabetic neuropathy with special reference to the interface that separate the endoneurial compartment from vascular and general extracellular spaces. To reach these goals, the specific aims of this proposal are to characterize the patterns of change in permeability of endoneurial capillaries during the early stages of experimental diabetic neuropathy. In adult diabetic rats, the i.v. bolus injection method will be used to measure the permeability of the capillary network in sciatic nerve to radioactive sodium and radioiodinated albumin - indices of capillary permeability to small and large blood-borne solutes, respectively. To detect small changes in permeability of individual capillaries that are beyond the resolution of whole nerve measurements, electrical resistance of individual endoneurial capillaries will be determined in another set of diabetic rats. Both permeability and resistance measurements will be performed in groups of rats 3 days to 6 months after successful induction of the diabetic state by an intraperitoneal injection of alloxan. Additionally, glycosylated hemoglobin, blood-glucose, and two indices of nerve pathology (nerve water content - index of nerve edema, and motor nerve conduction velocity) will be measured in the same groups of rats. By relating early increases in endoneurial capillary permeability with the earliest signs of nerve pathology, the results from these studies will help to elucidate the etiology of diabetic neuropathy, and provide information essential for the design of effective therapeutic interventions to alleviate the neuropathic complications of diabetes.